Background
Norwalk virus was officially renamed norovirus by the International Committee on Taxonomy of Viruses in 2002. The virions contain a single-stranded RNA molecule in round to hexagonal capsids that are 35-39 nm in diameter, with icosahedral symmetry. The surface structure of the capsid is a regular pattern with distinctive features and 32 cup-shaped depressions.[1, 2]
Norovirus was first recognized as a cause of gastroenteritis in 1972, when it was detected in stool samples collected from infected elementary school students and contacts during an outbreak in Norwalk, Ohio, in 1968. It was declared a member of the Caliciviridae family of viruses in 1993.[3] It is now considered the most common cause of epidemic nonbacterial gastroenteritis in the world.
In the 1970s and 1980s, typing of Norwalk-like virus (NLV) relied solely on immunologic methods involving human clinical samples as the source of antigens and antibodies. These methods had serious limitations in accuracy and reproducibility and never provided a reliable scheme for antigenic classification of strains. In the 1990s, however, newer molecular techniques to amplify, sequence, and express the genome of NLV strains allowed researchers to genetically and antigenically characterize NLV strains.[4]
The Norovirus genus contains more than 40 different strains that are divided into 5 genogroups based on sequence similarity. Viruses in genogroups I, II, and IV are primarily human pathogens, although genogroup II contains a porcine-specific virus. Viruses in genogroup III and V infect bovine and murine species, respectively. Each genogroup is further subdivided into genoclusters based on sequence similarity.[5]
The genome consists of single-stranded RNA of 7.3-7.7 kilobases. It encodes 3 open reading frames (ORFs). ORF 1 is the largest (approximately 1700 amino acids) and expressed as a nonstructural polyprotein precursor that is cleaved by the viral 3C-like protease. ORF 2 encodes the viral capsid (550 amino acids) and contains the shell and protruding domains. ORF 3 encodes a small basic protein of unknown function. See the image below.
The norovirus genomic structure and capsid domains. Pathophysiology
Noroviruses are transmitted person to person via direct contact, exposure to aerosols, or fecal–oral routes. Noroviruses are highly contagious, with infection requiring fever than 10 virions (ID50 = 10 virions), leading to disease in 50% of inoculated individuals. The virus is extremely stable in the environment and resists freezing temperatures, heat (up to 60˚C), disinfection with chlorine, acidic conditions, vinegar, alcohol, antiseptic hand solutions, and high sugar concentrations. The incubation period is approximately 1-2 days, and symptoms typically last 1-3 days (or longer in immunocompromised individuals). Viral shedding occurs for up to 3 weeks following infection.[6]
Noroviruses bind polymorphic histoblood group antigens (HBGAs) that putatively serve as receptors or cofactors for infection. Strains from different genoclusters bind various HBGAs: Genogroup I viruses preferentially bind blood group A and O antigens, while genogroup II viruses predominantly bind A and B antigens.[7] Individual norovirus strains may be capable of infecting only a subset of the human population, although the diverse binding profiles found within genogroup I and genogroup II viruses likely collectively make nearly all individuals susceptible to norovirus infection.[6] Recurrent infections can occur throughout life because of the great diversity of norovirus strains and the lack of cross-strain or long-term immunity.
Infection is characterized by damage to the microvilli in the small intestine. Upon microscopic investigation, villi are found to be blunted, although the mucosa and epithelium remain intact.[8] A recent study demonstrated increased epithelial cell apoptosis and damage to tight junction proteins.[9] Diarrhea is induced by D-xylose and fat malabsorption, with enzymatic dysfunction observed at the brush border, along with leak flux and anion secretion.[10, 9] Vomiting is related to virus-mediated changes in gastric motility and delayed gastric emptying. Notably, no histopathologic lesions can be identified in the gastric mucosa of infected patients.[11] Noroviruses do not invade the colon, so fecal leukocytes are typically absent, and hematochezia is rare.
Epidemiology
Frequency
United States
The Centers for Disease Control and Prevention (CDC) report that noroviruses account for more than 96% of all viral gastroenteritis cases, with at least 23 million infections occurring annually in the United States. Worldwide, noroviruses cause up to half of all outbreaks of gastroenteritis, making this the most common cause of sporadic diarrhea in community settings.[12]
According to surveillance reports prepared by CDC's OutbreakNet team, in 2006, 1,270 reported foodborne outbreaks resulted in 27,634 illnesses and 11 deaths. Among these 1,270 outbreaks, 621 had a single confirmed cause that was most often norovirus (54% of outbreaks), followed by Salmonella species (18% of outbreaks).[13]
Outbreaks have been reported in restaurants, health care facilities, schools, resorts, cruise ships, military ships, and barracks. Viral transmission occurs year-round, with a higher incidence of disease in winter months in temperate climates.[14]
International
Data regarding outbreaks in developing nations are not well quantified, but the outbreak rate in other industrial nations is similar to that of the United States.
Mortality/Morbidity
Norovirus gastroenteritis typically lasts 24-72 hours, with remission occurring without sequelae. Death is extremely rare, except in individuals particularly vulnerable to profound volume depletion.
Age
Norovirus gastroenteritis can occur in individuals of all ages. Studies using norovirus recombinant antigen have suggested an increase in antibody prevalence with advancing age. In one study, the prevalence of norovirus immunoglobulin G (IgG) rose during school-aged years, reaching a peak of 70% in persons aged 11-16 years.[15] It should be noted, however, that not all infected individuals sustain detectable antibody responses.
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